Multiple cyclophilins involved in different cellular pathways mediate HCV replication
Multiple cyclophilins involved in different cellular pathways mediate HCV replication
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DOI：
10.1016/j.virol.2009.10.043
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发表时间：
2010-02-05
期刊：
影响因子：
3.7
通讯作者：
Wiedmann, Brigitte
中科院分区：
文献类型：
--
作者：
Gaither, L. Alex;Borawski, Jason;Wiedmann, Brigitte
三种亲环素抑制剂（DEBIO-025，SCY 635和NIM 811）目前正在进行丙型肝炎治疗的临床试验。然而，这些的作用机制尚未完全了解。至少有16种亲环蛋白在人类细胞中表达，它们参与一系列不同的细胞过程。大规模的siRNA实验，与亲环蛋白结合化合物的化学蛋白质组学测定，和含HCV复制子的细胞的mRNA谱分析用于鉴定有助于HCV复制的亲环蛋白。证实了先前报道的亲环素A，并鉴定了另外的含有亲环素的途径。总之，这些实验提供了强有力的证据，表明NIM 811通过抑制多种亲环蛋白和蛋白质运输途径来减少病毒复制，蛋白质运输途径是最强烈和持续受影响的途径。(C)2009 Elsevier Inc. All rights reserved.
Three cyclophilin inhibitors (DEBIO-025, SCY635, and NIM811) are currently in clinical trials for hepatitis C therapy. The mechanism of action of these, however, is not completely understood. There are at least 16 cyclophilins expressed in human cells which are involved in a diverse set of cellular processes. Large-scale siRNA experiments, chemoproteomic assays with cyclophilin binding compounds, and mRNA profiling of HCV replicon containing cells were used to identify the cyclophilins that are instrumental to HCV replication. The previously reported cyclophilin A was confirmed and additional cyclophilin containing pathways were identified. Together, the experiments provide strong evidence that NIM811 reduces viral replication by inhibition of multiple cyclophilins and pathways with protein trafficking as the most strongly and persistently affected pathway. (C) 2009 Elsevier Inc. All rights reserved.